Synthesis of bromodifluoromethyl substituted pyrazoles and isoxazoles

Article abstract of DOI:10.1016/j.jfluchem.2009.12.017

Bromodifluoromethyl substituted β-diketone 3a-3d, prepared from corresponding ketones and ethyl bromodifluoroactate in the presence of sodium methoxide, reacted with aryl hydrazine derivatives affording bromodifluoromethyl substituted pyrazoles in high re

Full text of DOI:10.1016/j.jfluchem.2009.12.017

Journal of Fluorine Chemistry 131 (2010) 426–432
Contents lists available at ScienceDirect
Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Synthesis of bromodifluoromethyl substituted pyrazoles and isoxazoles
Xueyan Yang a, Shengxia Shui a, Xi Chen a, Hai’ou He a, Fanhong Wu a,b,c,
*
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals, East China University of Science and Technology, 130 Meilong Rd, Shanghai 200237, PR China
b The State Key Laboratory of Elemento-Organic Chemistry, Nankai University, PR China
c School of Chemical and Environmental Engineering, Shanghai Institute of Technology, 120 Caobao Rd., Shanghai 200235, PR China
A R T I C L E I N F O
A B S T R A C T
Article history:
Bromodifluoromethyl substituted
b-diketone 3a–3d, prepared from corresponding ketones and ethyl
Received 3 November 2009
Received in revised form 7 December 2009
Accepted 15 December 2009
Available online 23 December 2009
bromodifluoroactate in the presence of sodium methoxide, reacted with aryl hydrazine derivatives
affording bromodifluoromethyl substituted pyrazoles in high regioselectivity. The reaction of 3a–3d
with hydroxylamine hydrochloride gave dihydroisoxazoles, which afforded bromodifluoromethyl
substituted isoxazoles through dehydration by PPA or concentrated sulfuric acid.
ß 2010 Published by Elsevier B.V.
Keywords:
Bromodifluoromethyl
Pyrazoles
Isoxazoles
Regioselectivity
Synthesis
1. Introduction
this paper, we would like to report the reaction of bromodifluor-
omethyl substituted
b-diketones 3 and aryl hydrazine derivatives
There is an increasing interest in the synthesis of fluorinated
heterocyclic compounds in view of the potential biological
properties of such molecules [1–6]. The change is mainly due to
the high electronegativity of fluorine, the strong carbon–fluorine
bond, and increased lipid solubility. Fluorinated five-membered
heterocycles has been shown to be effective anti-tumor agents,
anti-malarials, enzyme inhibitors or precursor to antibiotics [7].
Fluorinated pyrazoles and isoxazoles are of particular interest to
the biochemical scientists because they exhibit various bioactiv-
ities [2,8–10]. Many examples have been reported on the synthesis
of trifluoromethyl substituted pyrazoles and isoxazoles, and such
compounds have found their applications in medicine and
agriculture [11]. However there are limited examples on the
synthesis of halodifluoromethyl substituted heterocyles, especially
pyrazoles and isoxazoles [11,12]. Prabhakaran et al. [11] and
Talley et al. [13] described the synthesis of bromodifluoromethyl
and chlorodifluoromethyl substituted pyrazoles from correspond-
4 or hydroxylamine hydrochloride to give the corresponding
bromodifluoromethyl substituted pyrazoles in high regioselec-
tivity or dihydroisoxazoles, which were dehydrated by PPA or
concentrated sulfuric acid to give isoxazoles.
2. Results and discussion
4-Bromo-4,4-difluoro-1-arylbutane-1,3-diones(3)wereobtained
from ketones 1 and ethyl bromodifluoroacetate 2 in the presence of
sodium methoxide in ethyl ether in 67–85% yields (Scheme 1). The
results arelistedinTable 1. The resultsshowed that thereactiongave
lower conversion of ketone 1 in absolute methanol or anhydrous
tetrahedydrofuran (Table 1, entries 2 and 3).
The condensation of 4-bromo-4,4-difluoro-1-phenylbutane-
1,3-diones (3aa) with phenylhydrazine (4aa) was investigated.
The reaction proceeded smoothly in anhydrous ethanol to give a
mixture of 5aa, 6aa, 7aa, 8aa (Scheme 2, Table 1, entries 1–4). The
ratio of 5aa/6aa was nearly equal to 7aa/8aa. In the presence of
different acids as catalyst, the content of 7aa and 8aa ranged from
18% to 25%. However, 7aa and 8aa decreased below 5% when the
reaction was carried out without any acid catalyst. It was found
that 7aa and 8aa was formed from the further reaction of 5aa and
6aa respectively, which could be illustrated by the increasing
content of 7aa and 8aa with longer reaction time. The results
showed that in refluxing ethanol containing concentrated sulfuric
acid the reaction afford a better product ratio of 5aa/6aa, which
ing
b-diketones and hydrazine derivatives respectively, however,
both in low yields. Halodifluoromethyl pyrazoles or isoxazoles
may have potential biological activities [12,14]. They also would be
very useful starting materials to build new difluoromethylated
pyrazoles or isoxazoles by the displacement of bromine [15–21]. In
* Corresponding author at: School of Chemical and Environmental Engineering,
Shanghai Institute of Technology, 120 Caobao Rd., Shanghai 200235, PR China.
E-mail address: wfh@ecust.edu.cn (F. Wu).
0022-1139/$ – see front matter ß 2010 Published by Elsevier B.V.
doi:10.1016/j.jfluchem.2009.12.017

X. Yang et al. / Journal of Fluorine Chemistry 131 (2010) 426–432
427
were summarized in Table 3. The regioselectivity of the reaction
varied from 94:6 to >99:1, which was obtained by analysis of 19
F
NMR of the crude reaction mixture. The product could be purified
by column chromatography eluted by a mixture of ethyl acetate
and petroleum ether or by recrystallization.
Scheme 1.
The reaction of 3 and excess hydroxylamine hydrochloride
was carried out for 3–6 h in ethanol or DMF to afford
dihydroisoxazoles 9 in isolated yields of 70–86% (Scheme 4
and Table 4). The compound 9 was dehydrated in PPA at 150–
160 8C or refluxed in butanol containing catalytic concentrated
sulfuric acid to give bromodifluoromethyl substituted isoxazoles
10 (Scheme 4).
Table 1
Data of the preparation of
b-diketone 3.
Entry
R1
Time
(h)
Solvent
Conversion
Products
Yieldsb
(%)
of 1a
1
2
3
4
5
6
Ph
48
48
48
30
40
18
Et2O
CH3OH
THF
83
29
26
60
70
87
3a
3a
3a
3b
3c
3d
83
–
Ph
The structures of 5aa and its regioisomer 6aa were deduced
from their NMR spectrums. The 1H NMR signal of the pyrazole 4-H
Ph
–
4-MePh
4-MeOPh
2-Thienyl
Et2O
Et2O
Et2O
67
80
85
of 5aa appeared at higher field (
regioisomer 6aa (
7.06 ppm, 1H, s). The 19F NMR signal of 5aa was
also at upfield (
d 6.72 ppm, 1H, s) than that of its
d
d
À43.6 ppm for 5aa and À40.3 ppm for 6aa). The
d
a
Based on GC.
results were in close agreement with the trifluoromethyl
substituted pyrazoles [7]. Further support for the structure of
5aa and 6aa was provided by the 13C NMR spectrum. For 5aa, the
b
Isolated yield and based on converted aryl ketone 1.
was similar to the reaction of trifluoromethyl substituted
diketones with phenylhydrazine [22].
b
-
signals of pyrazole 3-C (adjacent to CF2Br) appeared as a triplet at d
150.1 (2JC–F = 29.2 Hz) due to the coupling of the 3-C and fluorine.
For 6aa, the corresponding pyrazole 5-C (adjacent to CF2Br)
To avoid the formation of 7aa and 8aa and to obtain high
regioselectivity, the reaction was carried out in aprotic polar
solvent DMSO and DMF. As illustrated in Table 2, in DMSO or DMF
containing AcOH as catalyst, the reaction of 3aa and 4aa proceeded
smoothly to afford isomer 5aa as the main product with a trace of
6aa (Scheme 2 and Table 2, entries 5 and 6). However, a mixture of
5aa and 6aa in a ratio of 88:12 ratios was obtained in DMF in the
presence of 35% HCl (Scheme 2 and Table 1, entry 8). When DMF
containing concentrated sulfuric acid was used as the solvent, high
regioselectivity and higher yield of 5aa was achieved (Table 1,
entry 7).
showed a signal as a triplet at
d
140.8 (2JC–F = 30.6 Hz), in lower
field than that of 5aa.
The dihydropyrazoles were easily identified by NMR spectrosco-
py. For example, the 1H NMR spectrum of 9a displayed the
dihydropyrazole 4-CH2 protons as an AB system (doublets at
and
NMR,dihydropyrazole3-C,4-Cand5-Cdisplayedsignalsat
d
A 3.79
d
B 3.55, with the germinal coupling constant 2J = 17.8 Hz). In 13
C
d
d
157.8,
2
43.3 and
group in dihydroisoxazole been present at position-3, the signal at
107.4 would be appeared as a singlet instead of a triplet. Finally,
d 107.4 (t, JC–F = 27.4 Hz), respectively. Had the CF2Br
ꢀd
The reaction of 3 and 4a–d was carried out using DMF as the
solvent in the presence of concentrated sulfuric acid to give isomer
5 as the main product in moderate yields (Scheme 3). The results
the 19F NMR showed a typical AB system (doublets at dA À62.53 and
dB À63.65, with the germinal coupling constant 2JF–F = 166.4 Hz). For
11a, obtained form the dehydration of 9a, the signal of the isoxazole
Scheme 2.
Table 2
Reaction of
b-diketone 3a with phenyl hydrazine 4a.
Entry
Catalyst
Solvent
Temperature
Time (h)
Ratio of 5aa/6aaa
Content of 7a and 8a (%)b
Yields (%)c
1
2
3
4
5
6
7
8
AcOH
HCl
EtOH
EtOH
EtOH
EtOH
DMSO
DMF
DMF
DMF
Reflux
Reflux
Reflux
Reflux
100 8C
100 8C
100 8C
100 8C
3
3
3
3
3
2
3
6
82:18
60:40
64:36
82:18
>99:1
>99:1
>99:1
88:12
20
25
<5
18
–
57
73
85
81
63
61
86
53
–
H2SO4
AcOH
AcOH
H2SO4
HCl
–
–
–
a
Crude reaction mixture ratios based on 19F NMR.
Crude reaction mixture ratios based on 1H NMR.
Isolated yield of 5aa or a mixture.
b
c

428
X. Yang et al. / Journal of Fluorine Chemistry 131 (2010) 426–432
Scheme 3.
Table 3
Data of the reaction of 3 with nucleophilic reagents 4.
Entry
3
R1
4a
R2
Time (h)
Product
Yield (%)
Ratio of 5/6b
1
3a
3a
3a
3a
3b
3b
3b
3c
3c
3c
3c
3d
3d
3d
Ph
4a
4b
4c
4d
4a
4b
4c
4a
4b
4c
4d
4a
4b
4d
Ph
6
2
7
4
3
3
4
2
2
4
4
3
2
3
5aa
5ab
5ac
5ad
5ba
5bb
5bc
5ca
5cb
5cc
5cd
5da
5db
5dd
86
84
68
70
69
84
79
81
76
86
78
75
83
81
>99:1
>99:1
>99:1
>99:1
99:1
2
Ph
4-NH2SO2Ph
4-NO2Ph
3
Ph
4
Ph
4-MeNH2SO2CH2Ph
Ph
5
4-MePh
4-MePh
4-MePh
4-MeOPh
4-MeOPh
4-MeOPh
4-MeOPh
2-Thienyl
2-Thienyl
2-Thienyl
6
4-NH2SO2Ph
4-NO2Ph
>99:1
95:5
7
8
Ph
>99:1
>99:1
96:4
9
4-NH2SO2Ph
4-NO2Ph
10
11
12
13
14
4-MeNH2SO2CH2Ph
Ph
>99:1
94:6
4-NH2SO2Ph
4-MeNH2SO2CH2Ph
96:4
>99:1
a
4b and 4d was used as their hydrochloride.
Crude reaction mixture ratios based on 19F NMR.
b
Table 4
dihydroxytertrahydropyrazoles. One molecule of water is then
eliminated to give the hydroxydihydropyrazoles. Further elimi-
nation of water yields the aromatic pyrazoles 5 and 6. The ratio
of the two regioisomers mainly depends on the proportion of the
Reactions of
b-diketones 3 with hydroxylamine hydrochloride.
Entry
b-Diketone
Solvent
Reaction
time (h)
Yield
of 9 (%)a
Yield
of 10 (%)a,b
1
2
3
4
5
3a
3a
3b
3c
3d
EtOH
DMF
EtOH
EtOH
EtOH
4
10
3
86
78
82
82
84
78
–
71
80
81
4
5
a
Isolated yield.
b
Dehydrated by PPA.
Scheme 4.
4-CH proton appeared at
(t, J = 35.3 Hz).
d
6.92 (s, 1H) and the 5-C at 164.8
-diketones
Similar to trifluoromethyl substituted aryl
b
[23,24], 3 was supposed to exist in enol form and the direction
of enolization is largely towards COAr. It is therefore likely that
the reaction of 3 and 4 proceeds via conjugate addition of the
terminal nitrogen of the hydrazine derivatives into the two
enols (Scheme 5). Subsequent cyclization affords the isomeric
Scheme 5.

X. Yang et al. / Journal of Fluorine Chemistry 131 (2010) 426–432
429
3.1.2. 4-Bromo-4,4-difluoro-1-p-tolylbutane-1,3-dione (3b)
B.p. 135–137 8C/10 mmHg. 1H NMR (CDCl3)
: 15.0 (s, 1H),
d
7.85 (d, 2H, J = 8.16 Hz), 7.31 (d, 2H, J = 8.16 Hz), 6.48 (s, 1H),
2.44 (s, 3H) [11].
3.1.3. 4-Bromo-4,4-difluoro-1-(4-methoxyphenyl)butane-1,3-dione
(3c)
Pale yellow oil. B.p. 146–148 8C/5 mmHg. IR (film,
3121, 1590, 1507, 1459, 1269, 1182, 1145, 1101, 1067. 1H NMR
(CDCl3) : (enol) 15.5 (broad, 1H), 7.95–7.91 (m, 2H), 6.99–6.92 (m,
2H), 6.43 (s, 1H), 3.89 (s, 3H). 13C NMR (CDCl3)
: (enol) 184.9,
181.9 (t, J = 27.2 Hz), 165.1, 130.5, 125.7, 115.0, 114.4 (t,
J = 313.4 Hz), 89.5, 56.3. 19F NMR (CDCl3)
y
max, cmÀ1):
d
d
Scheme 6.
d
: À62.41 (s, 2F). HRMS
(EI): C11H9BrF2O3 calcd: 305.9706; found: 305.9723.
two enols at equilibrium, which was affected by solvent, acid
and temperature.
3.1.4. 4-Bromo-4,4-difluoro-1-(thiophen-2-yl)butane-1,3-dione (3d)
In the reaction of 3 and hydroxylamine hydrochloride, the
nucleophilic attack of NH2 of hydroxylamine takes place on the
carbonyl carbon attached to the aryl group (i.e. COAr) of the
diketones (Scheme 6), which was in conformity with the reaction
of trifluoromethyl substituted diketones and hydroxylamine
hydrochloride [25].
B.p. 117.0–119.0 8C/1.5 mmHg. IR (film,
1592, 1520, 1412, 1258, 1215, 1148, 1101, 1063, 944, 869, 724.
1H NMR (CDCl3)
: (enol, major) 14.9 (broad, 1H), 7.83 (dd, 1H,
y
max, cmÀ1): 3110,
d
J1 = 3.90 Hz, J2 = 1.10 Hz), 7.74 (dd, 1H, J1 = 5.00 Hz, J2 = 1.10 Hz),
7.20 (dd, 1H, J1 = 5.00 Hz, J2 = 3.90 Hz), 6.44 (s, 0.12H, E), 6.37 (s,
0.88H, Z); (ketone, minor) 7.80 (1H, dd, J1 = 3.90 Hz, J2 = 1.10 Hz),
7.70 (1H, dd, J1 = 4.90 Hz, J2 = 1.10 Hz), 7.18 (1H, dd, J1 = 4.90 Hz,
In summary, we reported a convenient synthesis of bromodi-
fluoromethyl substituted pyrazole and isoxazole derivatives in
J2 = 3.90 Hz), 3.72 (2H, s). 13C NMR (CDCl3)
d: (enol, major)
high regioselectivity using bromodifluoromethyl substituted
diketones 3 and aryl hydrazine derivatives 4 or hydroxylamine
hydrochloride.
b
-
181.3, 178.5 (t, J = 27.7 Hz), 139.2, 135.4, 133.1, 129.5, 113.9 (t,
J = 311.3 Hz), 94.0 (E), 91.0 (Z); (ketone, minor) 182.8, 186.2 (t,
J = 37.3 Hz), 140.5, 135.0, 132.7, 129.3, 117.8 (t, J = 268.8 Hz),
51.7. 19F NMR (CDCl3)
d
: (enol, major) À62.11 (s, 2F); (ketone,
minor) À84.58 (s, 2F). HRMS (EI): C8H5BrF2O2S calcd: 281.9162;
3. Experimental
found: 281.9153.
IR spectra were measured on
a Nicolet Magna IR-550
spectrometer. High-resolution mass spectra were carried out on
a Finnigan GC-MS-4021 spectrometer. NMR spectra were recorded
in CDCl3 solution at 20 8C on a Bruker AC-500 spectrometer
operating at 500 MHz (1H), 125.8 MHz (13C) and 470.5 MHz (19F).
3.2. General procedure for the preparation of bromodifluoromethyl
pyrazoles
The mixture of bromodifluoromethyl
b-diketone 3 (2 mmol),
Chemical shifts (
d
) are given in ppm relative to TMS for 1H and 13C,
solvent (10 mL), acid (0.05 mL), hydrazine derivative (2 mmol) was
stirred at room temperature for 2–5 h and then heated to 120 8C.
After stirring for 2–6 h at this temperature, the reaction mixture
was treated with water (10 mL) and extracted with ethyl acetate of
30 mL Â 3. After dried with sodium sulfate and removal of the
solvent, the residue was purified by recrystallization or column
chromatography eluted with a mixture of ethyl acetate and
petroleum oil.
and relative to CFCl3 for 19F. Column chromatography was
performed by using silica gel H, particle size 20–30
points are uncorrected.
mm. Melting
3.1. General procedure for the preparation of bromodifluoromethyl
b
-diketones 3
To the suspension of sodium methoxide (prepared from
sodium (6.9 g, 0.3 mol) and methanol) in ethyl ether (80 mL)
was added the mixture of ethyl bromodifluoromethyl acetate
(40.0 g, 0.2 mol), methyl ketone 1 (24 g, 0.2 mol) and ethyl ether
(120 mL) in 1 h. After stirring for 24–48 h at room temperature,
the reaction mixture was acidified to pH 2–3 with 1N HCl. The
organic layer was separated and washed with water and dried
with anhydrous sodium sulfate. After removal of ethyl ether, the
residue was distillated under vacuum to give bromodifluoro-
3.2.1. 3-(Bromodifluoromethyl)-1,5-diphenyl-1H-pyrazole (5aa)
Pale yellow oil (column). 1H NMR (CDCl3)
d
: 7.35–7.32 (m, 8H),
7.23–7.21 (m, 2H), 6.73 (s, 1H). 19F NMR (CDCl3)
d
: À43.4 (s, 2F).
3.2.2. Amixtureof3-(bromodifluoromethyl)-1,5-diphenyl-1H-pyrazole
(5aa) and 5-(bromodifluoromethyl)-1,3-diphenyl-1H-pyrazole (6aa)
Yellow oil (column). IR (film,
1500, 1272, 1207, 1115, 1087, 1073, 992. 1H NMR (CDCl3)
7.86–7.21 (m, 10H), 6.72 (s, 1H); (6aa) 7.86–7.21 (m, 10H), 7.06 (s,
1H). 13C NMR (CDCl3)
: (5aa) 150.1 (t, J = 29.2 Hz), 145.3, 139.9,
y
max, cmÀ1): 3133, 3058, 1595,
d
: (5aa)
methyl
b-diketone 3.
d
3.1.1. 4-Bromo-4,4-difluoro-1-phenylbutane-1,3-dione (3a)
B.p. 120–122 8C/5 mmHg. IR (film,
max, cmÀ1): 3120, 3064,
1604, 1571, 1491, 1255, 1187, 1152, 1110, 1094, 1066, 1001, 873,
759, 700, 685. 1H NMR (CDCl3)
: (enol) 14.9 (broad, 1H), 7.96–7.50
(m, 5H), 6.52 (s, 1H). 13C NMR (CDCl3)
: (enol, major) 184.7, 183.1
(t, J = 27.4 Hz), 134.5, 133.2, 129.6, 128.1, 114.1 (t, J = 313.9 Hz),
93.1 (E), 90.5 (Z); (ketone, minor) 185.4, 182.2 (t, J = 34.7 Hz),
134.1, 133.9, 129.5,128.0, 117.6 (t, J = 277.5 Hz), 51.7 (t, J = 6.8 Hz).
130.1, 129.8, 129.6, 129.4, 129.3, 127.5, 126.2, 115.1 (t,
J = 301.9 Hz), 105.5; (6aa) 151.8, 140.8 (t, J = 30.6 Hz), 140.0,
132.4, 129.8, 129.6, 129.4, 129.3, 129.1, 126.5, 111.6 (t,
y
d
J = 301.9 Hz), 105.5. 19F NMR (CDCl3)
d
: (5aa) À43.6 (s, 2F);
d
(6aa) À40.3 (s, 2F). HRMS (EI): C16H11N2F2Br cacld: 348.0074;
found: 348.0078.
3.2.3. 1,5-Diphenyl-1H-pyrazole-3-carboxylic acid ethyl ester (7aa)
[26,27]
19F NMR (CDCl3)
d
: (enol) À63.00 (s, 2F). HRMS (EI): C10H7BrF2O2
calcd: 275.9597; found: 275.9591. Only enol was observed in 1H
NMR and 19F NMR for the much lower concentration than in 13C
NMR.
White powder with mp 66.0–67.08C (column). 1H NMR (CDCl3)
d
: 7.35–7.21 (m, 10H), 7.05 (s, 1H), 4.46 (q, 2H, J = 7.10 Hz), 1.39 (t,
3H, J = 7.10 Hz). MS (EI): 292 (M+, 59.33), 247 (M+-OC2H5, 45.73),

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X. Yang et al. / Journal of Fluorine Chemistry 131 (2010) 426–432
220 (100), 219 (M+-COOC2H5, 70.32), 180 (18.87), 117 (14.14), 104
(16.05), 77 (Ph, 22.39).
3.2.10. 3-(Bromodifluoromethyl)-1-(4-nitrophenyl)-5-p-tolyl-1H-
pyrazole (5bc)
Colorless oil (column). IR (film,
1526, 1356, 1269, 1203, 1109, 1085, 992, 978. 1H NMR (CDCl3)
d:
y
max, cmÀ1): 3120, 3095, 1600,
3.2.4. 2,5-Diphenyl-2H-pyrazole-3-carboxylic acid ethyl ester (8aa)
[27]
8.23 (d, 2H, J = 9.01 Hz), 7.53 (d, 2H, J = 9.01 Hz), 7.19 (d, 2H,
J = 8.03 Hz), 7.14 (d, 2H, J = 8.03 Hz), 6.73 (s, 1H), 2.39 (s, 3H). 13C
White powder with mp 71.5–71.9 8C (column). 1H NMR (CDCl3)
d
: 7.89–7.33 (m, 10H), 7.33 (s, 1H), 4.27 (q, 2H, J = 7.10 Hz), 1.27 (t,
NMR (CDCl3)
130.1, 128.4, 127.3, 125.9, 125.7, 114.3 (t, J = 295.4 Hz), 105.4, 22.3.
19F NMR (CDCl3)
d: 151.9 (t, J = 29.20 Hz), 146.1, 143.0, 141.1, 139.4,
3H, J = 7.10 Hz). MS (EI): 292 (M+, 100), 264 (8.65), 263 (M+-C2H5,
11.8), 247 (M+-OC2H5, 12.9), 219 (M+-COOC2H5, 17.9), 117 (5.83),
116 (7.38), 77 (Ph, 7.86).
d
: À44.4 (s, 2F). HRMS (EI): C17H12BrF2N3O2 cacld:
407.0119; found: 407.0120.
3.2.5. 4-(3-(Bromodifluoromethyl)-5-phenyl-1H-pyrazol-1-yl)
3.2.11. 3-(Bromodifluoromethyl)-5-(4-methoxyphenyl)-1-phenyl-
benzenesulfonamide (5ab)
1H-pyrazole (5ca)
Yellow solid with mp 151.1–152.1 8C (column). IR (film, ymax
cmÀ1): 3342, 3266, 3141, 3080, 1598, 1506, 1322, 1206, 1160. 1
NMR (CDCl3) : 7.92 (d, 2H, J = 8.52 Hz), 7.49 (d, 2H, J = 8.52 Hz),
7.43–7.37 (m, 3H), 7.26–7.24 (m, 2H), 6.76 (s, 1H), 4.84 (s, 2H). 13
NMR (CDCl3) : 151.0 (t, J = 29.2 Hz), 145.8, 143.1, 142.1, 130.3,
129.7, 129.5, 129.3, 128.2, 126.2, 114.6 (t, J = 301.9 Hz), 106.6. 19
NMR (CDCl3)
,
H
Yellow oil (column). IR (film,
1595, 1577, 1552, 1499, 1253, 1206, 1177, 1086, 1032, 991, 862,
836. 1H NMR (CDCl3)
: 7.38–7.31(m, 5H), 7.14 (d, 2H, J = 8.8 Hz),
6.84 (d, 2H, J = 8.8 Hz), 6.67 (s, 1H), 3.80 (s, 3H). 13C NMR (CDCl3)
160.7, 150.0 (t, J = 29.1 Hz), 145.1, 140.0, 130.8, 129.7, 128.9, 126.2,
122.2, 115.2 (t, J = 295.4 Hz), 114.8, 104.9, 55.9. 19F NMR (CDCl3)
d:
y
max, cmÀ1): 3134, 3067, 1613,
d
d
C
d:
d
F
d
: À44.2 (s, 2F). HRMS (EI): C16H12BrF2N3O2S cacld:
À44.4 (s, 2F). HRMS (EI): C17H13N2OF2Br cacld: 378.0179; found:
426.9802; found: 426.9816.
378.0201.
3.2.6. 3-(Bromodifluoromethyl)-1-(4-nitrophenyl)-5-phenyl-1H-
3.2.12. 4-(3-(Bromodifluoromethyl)-5-(4-methoxyphenyl)-1H-
pyrazol-1-yl)benzenesulfonamide (5cb)
pyrazole (5ac)
Pale yellow oil (column). IR (film,
1596, 1524, 1346, 1270, 1206, 1110, 1087, 991, 971, 857. 1H NMR
(CDCl3) : 8.22 (d, 2H, J = 9.06 Hz), 7.52 (d, 2H, J = 9.06 Hz), 7.44–
y
max, cmÀ1): 3121, 3085,
White solid with mp 181.9–182.3 8C (from ethanol). IR (KBr,
y
max, cmÀ1): 3372, 3271, 2937, 2840, 1612, 1498, 1439, 1337,
d
1161 cmÀ1. 1H NMR (CDCl3)
J = 8.68 Hz), 7.15 (d, 2H, J = 8.74 Hz), 6.90 (d, 2H, J = 8.74 Hz), 6.70
(s, 1H), 4.87 (s, 2H), 3.84 (s, 3H). 13C NMR (CDCl3)
: 161.2, 150.9 (t,
J = 29.2 Hz), 145.7, 143.2, 142.0, 130.9, 128.1, 126.2, 121.5, 115.2,
114.7 (t, J = 301.9 Hz), 106.0, 56.0. 19F NMR (CDCl3)
d: 7.92 (d, 2H, J = 8.68 Hz), 7.50 (d, 2H,
7.38 (m, 3H), 7.25–7.24 (m, 2H), 6.77 (s, 1H). 19F NMR (CDCl3)
d:
À44.5 (s, 2F). 13C NMR (CDCl3)
d
: 151.4 (t, J = 29.7 Hz), 147.5, 145.9,
d
144.6, 130.4, 129.8, 129.5, 126.6, 126.1, 125.3, 114.6 (t,
J = 299.4 Hz), 106.9. HRMS (EI):
C
16H10N3O2F2Br cacld:
d
: À44.15 (s,
392.9924; found: 392.9922.
2F). HRMS (EI):
456.9909.
C17H14BrF2N3O3S cacld: 456.9907; found:
3.2.7. C-[4-(3-Bromodifluoromethyl-5-phenylpyrazol-1-yl)-phenyl]-
N-methyl-methanesulfonamide (5ad)
3.2.13. 3-(Bromodifluoromethyl)-5-(4-methoxyphenyl)-1-(4-
nitrophenyl)-1H-pyrazole (5cc)
White powder with mp 116.8–117.8 8C (column). IR (KBr,
y
max, cmÀ1): 3210, 1610, 1520, 1313, 1266, 1199, 1157, 1124,
Yellow solid with mp 122.3–122.7 8C (column). IR (KBr, ymax,
1086, 1069, 991, 864, 706, 665. 1H NMR (CDCl3)
(m, 9H), 6.74 (s, 1H), 4.26 (s, 2H), 4.05 (q, 1H, J = 5.00 Hz, NH),
2.68 (q, 3H, J = 5.00 Hz). 13C NMR (CDCl3)
: 150.4 (t, J = 29.1 Hz),
145.4, 140.2, 132.0, 130.3 129.9, 129.7, 129.5, 129.4, 126.4,
114.8 (t, J = 299.2 Hz), 105.8, 57.9, 30.6. 19F NMR (CDCl3)
d
: 7.41–7.22
cmÀ1): 3075, 1610, 1342, 1292, 1249, 1201, 1178, 1098, 1064,
1027, 991, 967, 859, 838. 1H NMR (CDCl3)
d: 8.21 (2H, d,
d
J = 8.98 Hz), 7.53 (2H, d, J = 8.98 Hz), 7.15 (2H, d, J = 8.69 Hz),
6.91 (2H, d, J = 8.69 Hz), 6.68 (s, 1H), 3.84 (s, 3H). 19F NMR (CDCl3)
d
:
d
: À44.4 (s, 2F). 13C NMR (CDCl3)
d: 161.3, 151.3 (t, J = 29.6 Hz),
À43.9 (s, 2F). HRMS (EI): C18H16N3O2F2S cacld: 455.0115; found:
147.4, 145.8, 144.7, 130.9, 126.0, 125.2, 121.5, 115.0, 114.6 (t,
455.0119.
J = 299.4 Hz), 106.4, 56.0. HRMS (EI): C17H12N3O3F2Br cacld:
423.0030; found: 423.0022.
3.2.8. 3-(Bromodifluoromethyl)-1-phenyl-5-p-tolyl-1H-pyrazole
(5ba)
3.2.14. C-{4-[3-Bromodifluoromethyl-5-(4-methoxy-phenyl)-
pyrazol-1-yl]-phenyl}-N-methyl-methanesulfonamide (5cd)
White powder with mp 138.0–140.0 8C (column).
IR (KBr,
1205, 1179, 1122, 1082, 991, 797, 722. 1H NMR (CDCl3)
d: 7.33 (d,
2H, J = 8.40 Hz), 7.27 (d, 2H, J = 8.40 Hz), 7.07 (d, 2H, J = 8.80 Hz),
6.77 (d, 2H, J = 8.80 Hz), 6.60 (s, 1H), 4.22 (q, 1H, J = 4.90 Hz), 4.17
(s, 2H), 3.74 (s, 3H), 2.60 (d, 3H, J = 4.90 Hz). 13C NMR (CDCl3)
d:
Colorless oil (column). IR (film,
1509, 1270, 1209, 1105, 1086, 1063. 1H NMR (CDCl3)
(m, 5H), 7.13–7.09 (m, 4H), 6.70 (s, 1H), 2.35 (s, 3H). 13C NMR
(CDCl3) : 150.9 (t, J = 29.2 Hz), 144.3, 139.2, 131.0, 129.7, 129.5,
129.2, 129.1, 127.5, 126.2, 115.2 (t, J = 301.9 Hz), 105.3, 21.5. 19F
NMR (CDCl3)
y
max, cmÀ1): 3123, 3068, 1605,
: 7.35–7.31
d
y
max, cmÀ1): 3234, 1611, 1502, 1319, 1273, 1253, 1234,
d
d
: À43.4 (s, 2F). HRMS (EI): C17H13BrF2N2, calcd:
362.0285; found: 362.0286.
160.9, 150.3 (t, J = 27.9 Hz), 145.3, 140.3, 132.0, 130.8, 130.2, 126.4,
121.9, 114.9, 112.5 (t, J = 279.6 Hz), 105.4, 58.0, 56.0, 30.5. 19F NMR
3.2.9. 4-(3-(Bromodifluoromethyl)-5-p-tolyl-1H-pyrazol-1-yl)
benzenesulfonamide (5bb) [11]
(CDCl3)
485.0220; found: 485.0221
d
: À43.8 (s, 2F). HRMS (EI): C19H18N3O3F2BrS cacld:
Yellow crystal with mp 176.0–177.0 8C (from PE:EA = 1:2).
IR (KBr,
1500, 1455, 1327. 1H NMR (CDCl3)
(d, 2H, J = 8.65 Hz), 7.18 (d, 2H, J = 8.03 Hz), 7.13 (d, 2H, J = 8.03 Hz),
6.73 (s, 1H), 4.82 (s, 2H), 2.39 (s, 3H). 13C NMR (CDCl3)
: 150.3 (t,
J = 29.3 Hz), 145.2, 142.6, 141.2, 139.8, 129.8, 128.7, 127.5, 125.7,
125.5, 114.2 (t, J = 301.9 Hz), 105.6, 21.3. 19F NMR (CDCl3)
y
max, cmÀ1): 3358, 3277, 3141, 3105, 2921, 1720, 1600,
d
: 7.90 (d, 2H, J = 8.65 Hz), 7.50
3.2.15. 3-(Bromodifluoromethyl)-1-phenyl-5-(thiophen-2-yl)-1H-
pyrazole (5da)
d
Yellow solid with mp 74.2–75.0 8C (column). IR (KBr, ymax,
cmÀ1): 3069, 1592, 1497, 1466, 1209, 1120, 989. 1H NMR (CDCl3)
d:
d
:
7.38–7.40 (m, 5H), 7.32 (1H, dd, J1 = 5.01 Hz, J2 = 1.11 Hz), 6.94 (1H,
dd, J1 = 5.01 Hz, J2 = 3.70 Hz), 6.86 (1H, dd, J1 = 3.71H, J2 = 1.11 Hz),
6.71 (s, 1H). 13C NMR (CDCl3)
d: 150.9 (t, J = 29.2 Hz), 138.9, 129.2,
À44.15 (s, 2F). HRMS (EI): C17H14BrF2N3O2S2, calcd: 440.9958;
found: 440.9958.

X. Yang et al. / Journal of Fluorine Chemistry 131 (2010) 426–432
431
128.1, 127.6, 127.4, 126.9, 126.4, 125.7, 124.9, 114.1 (t,
J = 301.9 Hz), 104.5. 19F NMR (CDCl3)
(EI): C14H9BrF2N2S cacld: 353.9638; found: 353.9641.
1146, 1109, 1070, 1044, 1018, 944, 914, 850, 829. 1H NMR (DMSO)
d: 7.72 (d, 2H, J = 8.55 Hz), 7.11 (d, 2H, J = 8.55 Hz), 3.90 (d, 1H,
d
: À43.7 (s, 2F). HRMS
J = 18.60 Hz), 3.83 (s, 3H), 3.58–3.47 (m, 1H). 19F NMR (CDCl3)
d:
À63.63 (d, J = 168.0 Hz), À64.62 (d, J = 168.0 Hz). 13C NMR (CDCl3)
3.2.16. 4-(3-(Bromodifluoromethyl)-5-(thiophen-3-yl)-1H-pyrazol-
1-yl)benzenesulfonamide (5db)
d: 162.3, 158.0, 129.6, 122.1 (t, J = 310.8 Hz), 121.2, 115.5, 108.0 (t,
J = 26.4 Hz), 56.4, 43.6. HRMS (EI): C11H10BrF2NO3 cacld: 320.9812;
White solid with mp 196.8–197.0 8C (from PE:EA = 3:1). IR (KBr,
found: 320.9830.
y
max, cmÀ1): 3353, 3218, 3099, 2922, 1559, 1345, 1163, 1092. 1H
NMR (CDCl3)
(d, 1H, J = 5.06 Hz), 7.03 (1H, dd, J1 = 5.06 Hz, J2 = 3.71 Hz), 6.92 (d,
1H, J = 3.71 Hz), 6.80 (s, 1H), 4.86 (s, 2H). 19F NMR (CDCl3)
: À44.39
(s, 2F). 13C NMR (CDCl3)
: 156.7 (t, J = 29.2 Hz), 151.2, 142.2, 141.9,
d
: 7.97 (d, 2H, J = 8.59 Hz), 7.59 (d, 2H, J = 8.59 Hz), 7.41
3.3.4. 5-(Bromodifluoromethyl)-3-(thiophen-2-yl)-4,5-
dihydroisoxazol-5-ol (9d)
d
White solid with mp 149.1–149.5 8C (from PE:EA = 50:1). IR
d
(KBr,
NMR (CDCl3) d: 7.48 (dd, 1H, J1 = 5.10 Hz, J2 = 1.10 Hz), 7.27 (dd,
y
max, cmÀ1): 3209 (broad), 3098, 2904, 2689, 1599, 1457. 1H
138.6, 128.9, 128.3, 127.9, 127.6, 126.2, 114.2 (t, J = 301.9 Hz), 106.2.
HRMS (EI): C14H10BrF2N3O2S2 calcd: 432.9366; found: 432.9369.
1H, J1 = 3.70 Hz, J2 = 1.10 Hz), 7.10 (dd, 1H, J1 = 5.10 Hz,
J2 = 3.70 Hz), 3.89 (d, 1H, J = 17.66 Hz), 3.56 (s, 1H), 3.54 (dt, 1H,
3.2.17. C-{4-[3-(Bromodifluoromethyl)-5-thiophen-3-yl-pyrazol-1-
yl]-phenyl}-N-methyl-methanesulfonamide (5dd)
J1 = 17.66 Hz, J2 = 1.36 Hz). 19F NMR (CDCl3)
d
:
À62.9 (d,
: 153.4,
J = 166.6 Hz), À63.7 (d, J = 166.6 Hz). 13C NMR (CDCl3)
d
Pale yellow powder with mp 164.8–165.1 8C (from ethanol). IR
130.7, 130.5, 130.3, 128.3, 121.2 (t, J = 312.6 Hz), 107.3 (t,
J = 27.4 Hz), 44.0. HRMS (EI): C8H6BrF2NO2S cacld: 296.9271;
found: 296.9264.
(KBr,
1123, 1091,992, 933, 864, 793, 700. 1H NMR(CDCl3)
y
max, cmÀ1): 3279, 3147, 1611, 1550, 1567, 1411, 1382, 1326,
d:7.49–6.36(m,
4H), 7.36 (dd, 1H, J1 = 5.10 Hz, J2 = 1.10 Hz), 6.99 (dd, 1H,
J1 = 5.10 Hz, J2 = 3.60 Hz), 6.91 (dd, 1H, J1 = 3.60 Hz, J2 = 1.10 Hz),
6.79 (1H, s), 4.28 (2H, s), 4.12 (1H, q, J = 4.30 Hz, NH), 2.72 (3H, d,
3.4. General procedure for the preparation of bromodifluoromethyl
isoxazoles
J = 4.30 Hz). 13C NMR (CDCl3)
d
: 150.3 (t, J = 29.6 Hz), 139.9, 139.3,
132.1, 131.2, 130.0, 129.1, 128.5, 128.3, 127.2, 114.6 (t, J = 299.3 Hz),
105.8, 58.0, 30.5. 19F NMR (CDCl3)
: À44.1 (2F, s). HRMS (EI):
16H14N3O2F2S2Br cacld: 460.9679; found: 460.9696.
The mixture of 9 (5 mmol) and PPA (3.0 g) was heated at 150 8C
for 30 min and then cooled to room temperature. After treated
with crushed ice (15 g), the reaction mixture was neutralized with
d
C
25% aqueous ammonia to pH
7 and then extracted with
3.3. General procedure for the preparation of bromodifluoromethyl
dihydroisoxazoles
trichloromethane of 20 mL Â 3. After dried with sodium sulfate
and removal of the solvent, the residue was purified by column
chromatography eluted with a mixture of ethyl acetate and
petroleum oil to give 10.
The mixture of bromodifluoromethyl
b-diketone 3 (2 mmol),
ethanol (10 mL), hydroxylamine hydrochloride (8 mmol) was
refluxed for 2–10 h. The reaction mixture was treated with water
(10 mL) and extracted with ethyl acetate of 30 mL Â 3. After dried
with sodium sulfate and removal of the solvent, the residue was
purified by recrystallization to give 9.
3.4.1. 5-(Bromodifluoromethyl)-3-phenylisoxazole (10a)
Pale yellow oil. IR (film,
1442, 1403, 1288, 1210, 1104, 994, 862. 1H NMR (CDCl3)
7.50 (m, 5H), 6.92 (s, 1H). 13C NMR (CDCl3)
: 164.8 (t, J = 33.2 Hz),
163.2, 131.5, 129.8, 128.1, 127.6, 109.9 (t, J = 299.9 Hz), 102.2. 19
NMR (CDCl3)
y
max, cmÀ1): 3137, 3067, 1610, 1580,
d
: 7.83–
d
F
3.3.1. 5-(Bromodifluoromethyl)-3-phenyl-4,5-dihydroisoxazol-5-ol
(9a)
d
: À48.90 (s, 2F). HRMS (EI): C10H6BrF2NO cacld:
272.9601; found: 272.9620.
White solid with mp 125.0–125.3 8C (from 30 to 60 petroleum
ether). IR (KBr,
1448, 127.9, 1242, 1210, 1142, 1063, 1013, 927, 850. 1H NMR
(CDCl3) : 7.69–7.43 (m, 5H), 3.79 (d, 1H, J = 17.87 Hz), 3.62 (br,
y
max, cmÀ1): 3180 (broad), 3042, 1636, 1610, 1574,
3.4.2. 5-(Bromodifluoromethyl)-3-p-tolylisoxazole (10b)
Pale yellow oil. IR (film,
1610, 1523, 1461, 1431, 1248. 1H NMR (CDCl3)
J = 8.10 Hz), 7.29 (d, 2H, J = 8.10 Hz), 6.87 (s, 1H), 2.42 (s, 3H). 13
NMR (CDCl3) : 171.4, 162.9 (t, J = 33.3 Hz), 141.9, 130.5, 126.6,
124.7, 113.1 (t, J = 300.7 Hz), 100.4, 20.4. 19F NMR (CDCl3)
y
max, cmÀ1): 3138, 3012, 2937, 2834,
d
d: 7.69 (d, 2H,
1H), 3.55 (dt, 1H, JH–H = 17.87 Hz, JH–F = 1.48 Hz). 19F NMR (CDCl3)
C
d
: À62.53 (d, 1F, J = 166.4 Hz), À63.65 (d, 1F, J = 166.4 Hz). 13C NMR
d
(CDCl3)
d
: 157.8, 131.8, 129.7, 128.7, 127.6, 121.4 (t, J = 312.8 Hz),
d
: À48.8
107.4 (t, J = 27.4 Hz), 43.3. HRMS (EI): C10H8NO2F2Br, cacld:
290.9706; found: 290.9710.
(s, 2F). HRMS (EI):
286.9759.
C11H8BrF2NO cacld: 286.9757; found:
3.3.2. 5-(Bromodifluoromethyl)-3-p-tolyl-4,5-dihydroisoxazol-5-ol
(9b)
3.4.3. 5-(Bromodifluoromethyl)-3-(4-methoxyphenyl)isoxazole (10c)
Pale yellow oil. IR (film, y
max, cmÀ1): 3135, 3006, 2936, 2839,
White solid with mp 121.2–121.7 8C (from PE:EA = 50:1). IR
1612, 1529, 1460, 1431, 1258. 1HNMR (CDCl3): 7.73 (d, 2H,
(KBr,
y
max, cmÀ1): 3182 (broad), 3041, 1634, 1610, 1584, 1458,
J = 8.75 Hz), 7.00 (d, 2H, J = 8.75 Hz), 6.86 (s, 1H), 3.86 (s, 3H). 19F
127.9, 1242, 1142, 1063, 927. 1H NMR (CDCl3)
d
: 7.54 (d, 2H,
NMR (CDCl3)
d
: À49.04 (s, 2F). 13C NMR (CDCl3)
d: 164.5 (t,
J = 7.95 Hz), 7.22 (d, 2H, J = 7.95 Hz), 3.82 (d, 1H, J = 17.40 Hz), 3.54
J = 33.2 Hz), 162.8, 162.3, 129.0, 120.5, 115.2, 109.9 (t,
(d, 1H, J = 17.40 Hz), 2.50 (s, 1H), 2.39 (s, 3H). 19F NMR (CDCl3)
À62.9 (d, J = 165.7 Hz), À63.7 (d, J = 165.7 Hz). 13C NMR (CDCl3)
d
d
:
:
J = 299.9 Hz), 102.0, 56.1. HRMS (EI): C11H8BrF2NO2 cacld:
302.9706; found: 302.9708.
161.8, 158.2, 129.5, 122.6 (t, J = 310.8 Hz), 121.5, 115.3, 108.2 (t,
J = 26.4 Hz), 56.4, 20.3. HRMS (EI): C11H10BrF2NO2 cacld: 304.9982;
found: 304.9984.
3.4.4. 5-(Bromodifluoromethyl)-3-(thiophen-2-yl)isoxazole (10d)
Pale yellow oil. IR (KBr,
max, cmÀ1): 3150, 2976, 2875, 1608,
1564, 1106. 1H NMR (CDCl3)
: 7.53–7.48 (m, 2H), 7.16 (dd, 1H,
J1 = 5.10 Hz, J2 = 3.60 Hz), 6.84 (s, 1H). 13C NMR (CDCl3)
: 164.1 (t,
J = 33.6 Hz), 157.7, 128.9, 128.8, 128.5, 127.9, 109.0 (t,
J = 300.1 Hz), 101.5. 19F NMR (CDCl3)
: À49.12 (s, 2F). HRMS
(EI): C8H4BrF2NOS cacld: 278.9165; found: 278.9165.
y
d
3.3.3. 5-(Bromodifluoromethyl)-3-(4-methoxyphenyl)-4,5-
dihydroisoxazol-5-ol (9c)
d
White solid with mp 110.9–111.1 8C (from PE:EA = 50:1). IR
d
(KBr,
y
max, cmÀ1): 3173 (broad), 1608, 1517, 1309, 1258, 1180,

432
X. Yang et al. / Journal of Fluorine Chemistry 131 (2010) 426–432
[11] J. Prabhakaran, M.D. Underwood, R.V. Parsey, V. Arango, V.J. Majo, N.R.
Acknowledgment
Simpson, R.V. Heertum, J.J. Mann, J.S. Dileep Kumar, Bioorg. Med. Chem. 15
(2007) 1802–1807.
We thank the National Natural Science Foundation of China
(Grant No. 20672034) for financial support.
[12] B.C. Hamper, K.L. Leschinsky, S.S. Massey, C.L. Bell, L.H. Brannigan, S.D. Prosch, J.
Agric. Food Chem. 43 (1995) 219–228.
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